Strucutral analysis of the membrane proteins involved in metal transport

• Project/Area Number: 18H02396
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 43020:Structural biochemistry-related
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: Sugimoto Hiroshi 国立研究開発法人理化学研究所, 放射光科学研究センター, 専任研究員 (90344043)
• Co-Investigator(Kenkyū-buntansha): 澤井 仁美 兵庫県立大学, 生命理学研究科, 助教 (50584851)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2020: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2018: ¥8,450,000 (Direct Cost: ¥6,500,000、Indirect Cost: ¥1,950,000)
• Keywords: ヘムタンパク質 / 電子伝達 / X線結晶構造解析 / ビタミンC / ヘム / X線

Outline of Final Research Achievements

Dietary iron absorption is regulated by duodenal cytochrome b (Dcytb), an integral membrane protein that catalyzes reduction of non-heme Fe (III) by electron transfer from ascorbate across the membrane. This step is essential to enable iron uptake by the divalent metal transporter. The current study provides structural insight into the function of Dcytb, one of the two duodenal proteins that are required for the uptake of dietary non-heme iron. In combination with the biochemical studies, this work also provides structural insight into how ascorbate enhances iron uptake and how several potential iron ligands found in various foods promote or inhibit iron uptake. Ultimately, knowledge of the structure of Dcytb should enable development of new, structure-based strategies for promoting the reduction of dietary iron and thereby enhancing the bioavailability of this essential nutrient.

Academic Significance and Societal Importance of the Research Achievements

鉄をはじめとする生体内の金属元素の多くはさまざまな生体内でのプロセスに必須であるが、過剰に体内に存在すると細胞にとって有毒となるため、体内の濃度は綿密に調整されている。本課題が実施したDcytbの解析では、ビタミンCによって小腸での鉄分の吸収が促進される仕組みを立体構造の見地から明らかにした。鉄の輸送と代謝のメカニズムは様々な疾病や病原菌の感染にも関与していることから注目されており、鉄過剰症や貧血といった制御のバランスが崩れて引き起こされる疾病の発症のメカニズムの理解や治療法の開発などへ発展すると期待される。

Research Products

• [Int'l Joint Research] University of British Columbia(カナダ)
• [Int'l Joint Research] University of Maryland(米国)
• [Int'l Joint Research] University of Maryland(米国)
• [Int'l Joint Research] University of British Columbia(カナダ)
• [Journal Article] Hemozoin produced by mammals confers heme tolerance (2019)
  • Author(s): Pek, R. H., Yuan, X., Rietzschel, N., Zhang, J., Jackson, L., Nishibori, E., Ribeiro, A., Simmons, W., Jagadeesh, J., Sugimoto, H., Alam, M. Z., Garrett, L., Haldar, M., Ralle, M., Phillips, J. D., Bodine, D. M., Hamza, I.
  • Journal Title: eLIFE Volume: 8
  • DOI: 10.7554/elife.49503
  • NAID: 120007127793
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Chemomechanical Coupling in the Transport Cycle of a Type II ABC Transporter (2019)
  • Author(s): K. Tamura, H. Sugimoto, Y. Shiro, Y. Sugita
  • Journal Title: J. Phys. Chem. B Volume: 123 Issue: 34 Pages: 7270-7281
  • DOI: 10.1021/acs.jpcb.9b04356
  • Peer Reviewed
• [Journal Article] Structural basis for promotion of duodenal iron absorption by enteric ferric reductase with ascorbate. (2018)
  • Author(s): Ganasen M, Togashi H, Takeda H, Asakura H, Tosha T, Yamashita K, Hirata K, Nariai Y, Urano T, Yuan X, Hamza I, Mauk AG, Shiro Y, Sugimoto H, Sawai H.
  • Journal Title: Communications Biology Volume: 1 Issue: 1 Pages: 120-120
  • DOI: 10.1038/s42003-018-0121-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] ヒトにおける鉄イオンの吸収に関わる膜タンパク質の構造機能相関と腸管細胞モデルでの機能評価系を用いた鉄イオン吸収を向上させる新たな化合物スクリーニング (2021)
  • Author(s): 澤井 仁美
  • Organizer: 日本薬学会第141年会 環境・衛生部会若手研究者シンポジウム
  • Invited
• [Presentation] 病原菌のヘム獲得のメカニズム (2020)
  • Author(s): 杉本 宏
  • Organizer: 第１５回トランスポーター研究会年会
  • Invited
• [Presentation] Reconstitution of full-complex of bacterial heme transporter into the platforms suitable for structural analysis (2020)
  • Author(s): Ayaho Abe, Hideki Shigematsu, Masaki Yamamoto, Yoshistugu Shiro, Hiroshi Sugimoto
  • Organizer: 日本蛋白質科学会年会
• [Presentation] Structural basis of iron reduction by human duodenal cytochrome b (Dcytb) involved in intestinal iron absorption (2019)
  • Author(s): Hiroshi Sugimoto, Menega Ganasen, Hiromi Togashi, Hanae Takeda, Yoshitsugu Shiro, A Grant Mauk, Hitomi Sawai
  • Organizer: 19th International Conference on Biological Inorganic Chemistry
  • Int'l Joint Research
• [Presentation] Structural basis of ascorbate-dependent iron reduction by human Dcytb involved in intestinal iron absorption (2019)
  • Author(s): Hiroshi Sugimoto, Menega Ganasen, Hiromi Togashi, Hanae Takeda, Yoshitsugu Shiro, A Grant Mauk, Hitomi Sawai
  • Organizer: 32nd European Crystallographic Meeting
  • Int'l Joint Research
• [Presentation] ヒト小腸の細胞膜でDcytbが鉄分吸収を促進するメカニズム (2018)
  • Author(s): Menega Ganasen、冨樫ひろ美、山下恵太郎、平田邦生、Grant A. Mauk、城 宜嗣、澤井仁美、杉本 宏
  • Organizer: 平成30年度結晶学会年会
• [Presentation] ヒトの鉄イオン吸収に関わる膜タンパク質の立体構造に基づく生きた細胞での機能解析 (2018)
  • Author(s): M. Ganasen, 藤代瞳、X. Yuan, I. Hamza, 姫野誠一郎、A. G. Mauk, 杉本宏、城宜嗣、澤井仁美
  • Organizer: メタルバイオサイエンス研究会2018
• [Presentation] ヒトの鉄イオン吸収に関わる膜タンパク質の立体構造を基盤とした機能と構造の相互解析 (2018)
  • Author(s): 澤井仁美
  • Organizer: 第42回日本鉄バイオサイエンス学会学術集会
• [Presentation] Structural Basis for Promotion of Human Iron Absorption by Duodenal Ferric Reductase with Ascorbate and Some Dietary Metal-chelators (2018)
  • Author(s): H. Sawai
  • Organizer: Cold Spring Harbor Asia Meeting: Iron, Reactive Oxygen Species & Ferroptosis in Life, Death & Disease
  • Int'l Joint Research
• [Presentation] Structural Basis for Enhancement of Human Iron Uptake by Duodenal Ferric Reductase with Ascorbate (2018)
  • Author(s): H. Sawai
  • Organizer: 9th Asian Biological Inorganic Chemistry (AsBIC-9)
  • Int'l Joint Research
• [Presentation] Structural Insight into the Dietary Non-heme Iron Absorption in Human Duodenum (2018)
  • Author(s): M. Ganasen, H. Asakura, T. Tosha, X. Yuan, I. Hamza, A. G. Mauk, Y. Shiro, H. Sugimoto and H. Sawai
  • Organizer: 第18回日本蛋白質科学会年会
• [Presentation] Structure-guided Functional Analysis of Human Ferric Reductase Using Living Cells (2018)
  • Author(s): Menega Ganasen, Hitomi Fujishiro, Xiaojing Yuan, Iqbal Hamza, A. Grant Mauk, Seiichiro Himeno, Hiroshi Sugimoto, Yoshitsugu Shiro, Hitomi Sawai
  • Organizer: Gordon Research Conference: 2018 Chemistry and Biology of Tetrapyrroles
  • Int'l Joint Research
• [Presentation] Understanding the Mechanism of Dietary Iron Absorption at the Atomic level (2018)
  • Author(s): M. Ganasen, H. Asakura, T. Tosha, T. Urano, X. Yuan, I. Hamza, A. G. Mauk, Y. Shiro, H. Sugimoto, H. Sawai
  • Organizer: 第91回日本生化学会年会
• [Presentation] 小腸上皮細胞膜で機能する鉄還元酵素Dcytbの結晶構造 (2018)
  • Author(s): 杉本宏, Menega Ganasen 冨樫ひろ美，武田英恵, 朝倉帆南, 山下恵太郎，平田邦生， A. Grant Mauk，城宜嗣，澤井仁美
  • Organizer: 平成30年度 内外環境応答・代謝酵素研究会
• [Presentation] Structural basis of ascorbate-dependent iron reduction by human duodenal cytochrome b (Dcytb) involved in intestinal iron absorption (2018)
  • Author(s): H. Sugimoto, M. Ganesen, H. Togashi, H. Takeda, H. Asakura, T. Tosha, K. Yamashita, K. Hirata, X. Yuan, I. Hamza, A. G. Mauk, Y. Shiro, H. Sawai
  • Organizer: Asian Crystallographic Association Conference (AsCA 2018)
  • Int'l Joint Research
• [Remarks] 貧血予防に新たな指針～ビタミンCが鉄分の吸収を促進するメカニズムを原子レベルで解明～
  • URL: http://www.riken.jp/pr/press/2018/20180820_1/
• [Remarks] 貧血予防に新たな指針 ～ ビタミンＣが鉄分の吸収を促進するメカニズムを原子レベルで解明 ～
  • URL: http://www.spring8.or.jp/ja/news_publications/press_release/2018/180820/